US 12,285,490 B2
ASH1L degraders and methods of treatment therewith
Jolanta Grembecka, Ann Arbor, MI (US); Szymon Klossowski, Ann Arbor, MI (US); Jing Deng, Ann Arbor, MI (US); Tomasz Cierpicki, Ann Arbor, MI (US); Hao Li, Ann Arbor, MI (US); Hongzhi Miao, Ann Arbor, MI (US); Trupta Purohit, Ann Arbor, MI (US); EunGi Kim, Ann Arbor, MI (US); and Dong Chen, Ann Arbor, MI (US)
Assigned to The Regents of the University of Michigan, Ann Arbor, MI (US)
Filed by The Regents of the University of Michigan, Ann Arbor, MI (US)
Filed on Oct. 17, 2023, as Appl. No. 18/488,912.
Application 18/488,912 is a continuation of application No. 17/468,308, filed on Sep. 7, 2021, granted, now 11,786,602, issued on Oct. 17, 2023.
Application 17/468,308 is a continuation of application No. 16/186,012, filed on Nov. 9, 2018, granted, now 11,110,177, issued on Sep. 7, 2021.
Claims priority of provisional application 62/584,473, filed on Nov. 10, 2017.
Prior Publication US 2024/0366774 A1, Nov. 7, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/64 (2017.01); A61K 9/00 (2006.01); A61K 31/404 (2006.01); A61K 31/454 (2006.01); A61K 31/4545 (2006.01); A61K 38/45 (2006.01); A61K 47/54 (2017.01); A61P 35/02 (2006.01); C07D 209/24 (2006.01); C07D 471/04 (2006.01)
CPC A61K 47/64 (2017.08) [A61K 9/0019 (2013.01); A61K 9/0053 (2013.01); A61K 31/404 (2013.01); A61K 31/454 (2013.01); A61K 31/4545 (2013.01); A61K 38/45 (2013.01); A61K 47/545 (2017.08); A61K 47/556 (2017.08); A61P 35/02 (2018.01); C07D 209/24 (2013.01); C07D 471/04 (2013.01); C12Y 203/02 (2013.01)] 19 Claims
 
1. A method of treating cancer comprising administering to a subject suffering from cancer with a proteolysis targeting chimera (PROTAC) compound capable binding to ASH1L and an E3 ligase complex, the PROTAC compound comprising a structure of:

OG Complex Work Unit Chemistry
wherein X is CH or N;
wherein Z is S or O;
wherein R1 is selected from

OG Complex Work Unit Chemistry
wherein R9 and R10, when present in an R1 substituent, are independently selected from H, CH3, F, CFH2, CF2H, CF3, and OH;
wherein R8, when present in an R1 substituent, is selected from

OG Complex Work Unit Chemistry
wherein R11, when present in an R8 substituent, is selected from

OG Complex Work Unit Chemistry
wherein R2-R5 and R7 are independently selected from H, halogen, CH3, OH, SH, NH2, CN, CF3, CCl3, —CH2—CH3, —CH2—OH, —CH2NH2, CH3SH, CH2Cl, CH2Br, CH2F, CHF2, CH2CN, CH2CF3, and CH2Cl3;
wherein A is

OG Complex Work Unit Chemistry
wherein Ligase Ligand is a moiety capable of binding to the E3 ligase complex; and
wherein Linker is a functional group tethering the Ligase Ligand to A;
or a salt thereof.